Cognate interactions between T cells and antigen presenting cells (APCs) involve a variety of accessory and adhesion molecules and cytokines that pattern the response to the presented antigens. In addition, expression of certain accessory molecules, such as Fas (CD95) and Fas-ligand, are essential for proper immune clearance of activated cells. We have found that the affected joints of patients with well-established rheumatoid arthritis (RA) represent "immune underprivileged sites" that harbor activated mononuclear cells that constitutively over-express stimulatory immune accessory molecules and cytokines. Furthermore, we recently have found evidence for defective clearance of such cells resulting from an acquired deficiency in expression of functional Fas-ligand in the diseased synovium. This defect may result from impaired expression of Fas-ligand mRNA and/or rapid proteolysis of Fas-ligand protein. Finally, we hypothesize that strategies aimed at reversing his acquired deficiency and/or reducing the expression of co-stimulatory immune accessory molecules will ameliorate the established phase of this disease. Accordingly, this proposal has the following specific aims: 1) examine the induction-kinetics of Fas-Ligand (Fas-L) mRNA and surface protein expression by blood and synovial lymphocytes of persons with RA and normal controls; 2) examine the stability of native Fas-L and Fas-L deletion mutants lacking the metalloproteinase cleavage site(s) under conditions within diseased joints of persons with RA; 3) generate and test viral vectors encoding native or truncated Fas-L, IL-10, or IL-13; and 4) examine whether vectors encoding native or truncated Fas-L, IL-10, and/or IL-13 can ameliorate pathology in experimental animals induced to develop arthritis. Through this work we may develop effective new strategies for immune gene therapy of patients with established RA.